BACKGROUND: Promotion of myelin repair in the context of demyelinating diseases such as multiple sclerosis (MS) still represents a clinical unmet need, given that this disease is not only characterized by autoimmune activities but also by impaired regeneration processes. Hence, this relates to replacement of lost oligodendrocytes and myelin sheaths-the primary targets of autoimmune attacks. Endogenous remyelination is mainly mediated via activation and differentiation of resident oligodendroglial precursor cells (OPCs), whereas its efficiency remains limited and declines with disease progression and aging. Teriflunomide has been approved as a first-line treatment for relapsing remitting MS. Beyond its role in acting via inhibition of de novo pyrimidine synthesis leading to a cytostatic effect on proliferating lymphocyte subsets, this study aims to uncover its potential to foster myelin repair. METHODS: Within the cuprizone mediated de-/remyelination model teriflunomide dependent effects on oligodendroglial homeostasis and maturation, related to cellular processes important for myelin repair were analyzed in vivo. Teriflunomide administration was performed either as pulse or continuously and markers specific for oligodendroglial maturation and mitochondrial integrity were examined by means of gene expression and immunohistochemical analyses. In addition, axon myelination was determined using electron microscopy. RESULTS: Both pulse and constant teriflunomide treatment efficiently boosted myelin repair activities in this model, leading to accelerated generation of oligodendrocytes and restoration of myelin sheaths. Moreover, teriflunomide restored mitochondrial integrity within oligodendroglial cells. CONCLUSIONS: The link between de novo pyrimidine synthesis inhibition, oligodendroglial rescue, and maintenance of mitochondrial homeostasis appears as a key for successful myelin repair and hence for protection of axons from degeneration.

Brain and Mind Center University of Sydney Sydney Australia

Department of General Pediatrics Neonatology and Pediatric Cardiology Medical Faculty Heinrich Heine University Düsseldorf Germany

Department of Neurology Medical Faculty Heinrich Heine University Moorenstrasse 5 40225 Düsseldorf Germany

Department of Neurology Palacky University Olomouc Olomouc Czech Republic

Department of Neurology Section of Developmental Neurobiology University Hospital Würzburg Germany

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Lassmann H. Multiple sclerosis pathology. Cold Spring Harb Perspect Med. 2018;8(3):a028936. PubMed PMC

Franklin RJ, Ffrench-Constant C. Remyelination in the CNS: from biology to therapy. Nat Rev Neurosci. 2008;9(11):839–855. PubMed

Zawadzka M, Rivers LE, Fancy SP, Zhao C, Tripathi R, Jamen F, et al. CNS-resident glial progenitor/stem cells produce Schwann cells as well as oligodendrocytes during repair of CNS demyelination. Cell Stem Cell. 2010;6(6):578–590. PubMed PMC

Gensert JM, Goldman JE. Endogenous progenitors remyelinate demyelinated axons in the adult CNS. Neuron. 1997;19(1):197–203. PubMed

Simons M, Nave KA. Oligodendrocytes: myelination and axonal support. Cold Spring Harb Perspect Biol. 2015;8(1):a020479. PubMed PMC

Bezukladova S, Genchi A, Panina-Bordignon P, Martino G. Promoting exogenous repair in multiple sclerosis: myelin regeneration. Curr Opin Neurol. 2022;35(3):313–318. PubMed

Lubetzki C, Zalc B, Kremer D, Küry P. Endogenous clues promoting remyelination in multiple sclerosis. Curr Opin Neurol. 2022;35(3):307–312. PubMed

Manousi A, Küry P. Small molecule screening as an approach to encounter inefficient myelin repair. Curr Opin Pharmacol. 2021;61:127–135. PubMed

Küry P, Kremer D, Göttle P. Drug repurposing for neuroregeneration in multiple sclerosis. Neural Regen Res. 2018;13(8):1366–1367. PubMed PMC

Claussen MC, Korn T. Immune mechanisms of new therapeutic strategies in MS: teriflunomide. Clin Immunol. 2012;142(1):49–56. PubMed

O'Connor P, Wolinsky JS, Confavreux C, Comi G, Kappos L, Olsson TP, et al. Randomized trial of oral teriflunomide for relapsing multiple sclerosis. N Engl J Med. 2011;365(14):1293–1303. PubMed

Confavreux C, O'Connor P, Comi G, Freedman MS, Miller AE, Olsson TP, et al. Oral teriflunomide for patients with relapsing multiple sclerosis (TOWER): a randomised, double-blind, placebo-controlled, phase 3 trial. Lancet Neurol. 2014;13(3):247–256. PubMed

Bruneau JM, Yea CM, Spinella-Jaegle S, Fudali C, Woodward K, Robson PA, et al. Purification of human dihydro-orotate dehydrogenase and its inhibition by A77 1726, the active metabolite of leflunomide. Biochem J. 1998;336(Pt 2):299–303. PubMed PMC

Cherwinski HM, Cohn RG, Cheung P, Webster DJ, Xu YZ, Caulfield JP, et al. The immunosuppressant leflunomide inhibits lymphocyte proliferation by inhibiting pyrimidine biosynthesis. J Pharmacol Exp Ther. 1995;275(2):1043–1049. PubMed

Zhang J, Teran G, Popa M, Madapura H, Ladds M, Lianoudaki D, et al. DHODH inhibition modulates glucose metabolism and circulating GDF15, and improves metabolic balance. iScience. 2021;24(5):102494. PubMed PMC

Göttle P, Manousi A, Kremer D, Reiche L, Hartung HP, Küry P. Teriflunomide promotes oligodendroglial differentiation and myelination. J Neuroinflammation. 2018;15(1):76. PubMed PMC

Martin E, Aigrot MS, Lamari F, Bachelin C, Lubetzki C, NaitOumesmar B, et al. Teriflunomide promotes oligodendroglial 8,9-unsaturated sterol accumulation and CNS remyelination. Neurol Neuroimmunol Neuroinflamm. 2021 doi: 10.1212/NXI.0000000000001091. PubMed DOI PMC

Matsushima GK, Morell P. The neurotoxicant, cuprizone, as a model to study demyelination and remyelination in the central nervous system. Brain Pathol. 2001;11(1):107–116. PubMed PMC

Ringheim GE, Lee L, Laws-Ricker L, Delohery T, Liu L, Zhang D, et al. Teriflunomide attenuates immunopathological changes in the dark agouti rat model of experimental autoimmune encephalomyelitis. Front Neurol. 2013;4:169. PubMed PMC

Groh J, Horner M, Martini R. Teriflunomide attenuates neuroinflammation-related neural damage in mice carrying human PLP1 mutations. J Neuroinflammation. 2018;15(1):194. PubMed PMC

Nair AB, Jacob S. A simple practice guide for dose conversion between animals and human. J Basic Clin Pharm. 2016;7(2):27–31. PubMed PMC

Chen Z, Chen JT, Johnson M, Gossman ZC, Hendrickson M, Sakaie K, et al. Cuprizone does not induce CNS demyelination in nonhuman primates. Ann Clin Transl Neurol. 2015;2(2):208–213. PubMed PMC

Nakatani H, Martin E, Hassani H, Clavairoly A, Maire CL, Viadieu A, et al. Ascl1/Mash1 promotes brain oligodendrogenesis during myelination and remyelination. J Neurosci. 2013;33(23):9752–9768. PubMed PMC

Göttle P, Sabo JK, Heinen A, Venables G, Torres K, Tzekova N, et al. Oligodendroglial maturation is dependent on intracellular protein shuttling. J Neurosci. 2015;35(3):906–919. PubMed PMC

Pavic G, Petzsch P, Jansen R, Raba K, Rychlik N, Simiantonakis I, et al. Microglia contributes to remyelination in cerebral but not spinal cord ischemia. Glia. 2021;69(11):2739–2751. PubMed

Groh J, Friedman HC, Orel N, Ip CW, Fischer S, Spahn I, et al. Pathogenic inflammation in the CNS of mice carrying human PLP1 mutations. Hum Mol Genet. 2016;25(21):4686–4702. PubMed

Chaudhry A, Shi R, Luciani DS. A pipeline for multidimensional confocal analysis of mitochondrial morphology, function, and dynamics in pancreatic beta-cells. Am J Physiol Endocrinol Metab. 2020;318(2):E87–E101. PubMed PMC

Hemel I, Engelen BPH, Luber N, Gerards M. A hitchhiker's guide to mitochondrial quantification. Mitochondrion. 2021;59:216–224. PubMed

Faul F, Erdfelder E, Buchner A, Lang AG. Statistical power analyses using G*Power 3.1: tests for correlation and regression analyses. Behav Res Methods. 2009;41(4):1149–1160. PubMed

Xing YL, Roth PT, Stratton JA, Chuang BH, Danne J, Ellis SL, et al. Adult neural precursor cells from the subventricular zone contribute significantly to oligodendrocyte regeneration and remyelination. J Neurosci. 2014;34(42):14128–14146. PubMed PMC

Bujalka H, Koenning M, Jackson S, Perreau VM, Pope B, Hay CM, et al. MYRF is a membrane-associated transcription factor that autoproteolytically cleaves to directly activate myelin genes. PLoS Biol. 2013;11(8):e1001625. PubMed PMC

Spaas J, van Veggel L, Schepers M, Tiane A, van Horssen J, Wilson DM, 3rd, et al. Oxidative stress and impaired oligodendrocyte precursor cell differentiation in neurological disorders. Cell Mol Life Sci. 2021;78(10):4615–4637. PubMed PMC

Corona JC, Duchen MR. PPARgamma as a therapeutic target to rescue mitochondrial function in neurological disease. Free Radic Biol Med. 2016;100:153–163. PubMed PMC

Yeligar SM, Kang BY, Bijli KM, Kleinhenz JM, Murphy TC, Torres G, et al. PPARgamma regulates mitochondrial structure and function and human pulmonary artery smooth muscle cell proliferation. Am J Respir Cell Mol Biol. 2018;58(5):648–657. PubMed PMC

Sidarala V, Zhu J, Levi-D'Ancona E, Pearson GL, Reck EC, Walker EM, et al. Mitofusin 1 and 2 regulation of mitochondrial DNA content is a critical determinant of glucose homeostasis. Nat Commun. 2022;13(1):2340. PubMed PMC

Gao F, Reynolds MB, Passalacqua KD, Sexton JZ, Abuaita BH, O'Riordan MXD. The mitochondrial fission regulator DRP1 controls post-transcriptional regulation of TNF-alpha. Front Cell Infect Microbiol. 2020;10:593805. PubMed PMC

Lisowski P, Kannan P, Mlody B, Prigione A. Mitochondria and the dynamic control of stem cell homeostasis. EMBO Rep. 2018;19(5):e45432. PubMed PMC

Peng F, Wang JH, Fan WJ, Meng YT, Li MM, Li TT, et al. Glycolysis gatekeeper PDK1 reprograms breast cancer stem cells under hypoxia. Oncogene. 2018;37(8):1119. PubMed PMC

Xie H, Hanai J, Ren JG, Kats L, Burgess K, Bhargava P, et al. Targeting lactate dehydrogenase–a inhibits tumorigenesis and tumor progression in mouse models of lung cancer and impacts tumor-initiating cells. Cell Metab. 2014;19(5):795–809. PubMed PMC

Dupuy F, Tabaries S, Andrzejewski S, Dong Z, Blagih J, Annis MG, et al. PDK1-dependent metabolic reprogramming dictates metastatic potential in breast cancer. Cell Metab. 2015;22(4):577–589. PubMed

Prigione A, Rohwer N, Hoffmann S, Mlody B, Drews K, Bukowiecki R, et al. HIF1alpha modulates cell fate reprogramming through early glycolytic shift and upregulation of PDK1-3 and PKM2. Stem Cells. 2014;32(2):364–376. PubMed PMC

Bar-Or A, Pachner A, Menguy-Vacheron F, Kaplan J, Wiendl H. Teriflunomide and its mechanism of action in multiple sclerosis. Drugs. 2014;74(6):659–674. PubMed PMC

Lu Z, Zhang D, Cui K, Fu X, Man J, Lu H, et al. Neuroprotective action of teriflunomide in a mouse model of transient middle cerebral artery occlusion. Neuroscience. 2020;428:228–241. PubMed

Freedman MS, Wolinsky JS, Comi G, Kappos L, Olsson TP, Miller AE, et al. The efficacy of teriflunomide in patients who received prior disease-modifying treatments: subgroup analyses of the teriflunomide phase 3 TEMSO and TOWER studies. Mult Scler. 2018;24(4):535–539. PubMed PMC

Barcelos IP, Troxell RM, Graves JS. Mitochondrial dysfunction and multiple sclerosis. Biology (Basel). 2019;8(2):37. PubMed PMC

Zhao JW, Wang DX, Ma XR, Dong ZJ, Wu JB, Wang F, et al. Impaired metabolism of oligodendrocyte progenitor cells and axons in demyelinated lesion and in the aged CNS. Curr Opin Pharmacol. 2022;64:102205. PubMed

Rinholm JE, Vervaeke K, Tadross MR, Tkachuk AN, Kopek BG, Brown TA, et al. Movement and structure of mitochondria in oligodendrocytes and their myelin sheaths. Glia. 2016;64(5):810–825. PubMed

Bertholet AM, Delerue T, Millet AM, Moulis MF, David C, Daloyau M, et al. Mitochondrial fusion/fission dynamics in neurodegeneration and neuronal plasticity. Neurobiol Dis. 2016;90:3–19. PubMed

Meyer N, Rinholm JE. Mitochondria in myelinating oligodendrocytes: slow and out of breath? Metabolites. 2021;11(6):359. PubMed PMC

Marangon D, Boccazzi M, Lecca D, Fumagalli M. Regulation of oligodendrocyte functions: targeting lipid metabolism and extracellular matrix for myelin repair. J Clin Med. 2020;9(2):470. PubMed PMC

Poitelon Y, Kopec AM, Belin S. Myelin fat facts: an overview of lipids and fatty acid metabolism. Cells. 2020;9(4):812. PubMed PMC

Tepavcevic V. Oligodendroglial energy metabolism and (re)myelination. Life. 2021;11(3):238. PubMed PMC

Schoenfeld R, Wong A, Silva J, Li M, Itoh A, Horiuchi M, et al. Oligodendroglial differentiation induces mitochondrial genes and inhibition of mitochondrial function represses oligodendroglial differentiation. Mitochondrion. 2010;10(2):143–150. PubMed PMC

Yazdankhah M, Shang P, Ghosh S, Bhutto IA, Stepicheva N, Grebe R, et al. Modulating EGFR-MTORC1-autophagy as a potential therapy for persistent fetal vasculature (PFV) disease. Autophagy. 2020;16(6):1130–1142. PubMed PMC

Tondera D, Grandemange S, Jourdain A, Karbowski M, Mattenberger Y, Herzig S, et al. SLP-2 is required for stress-induced mitochondrial hyperfusion. EMBO J. 2009;28(11):1589–1600. PubMed PMC

Mari M, Colell A. Mitochondrial oxidative and nitrosative stress as a therapeutic target in diseases. Antioxidants. 2021;10(2):314. PubMed PMC

Rojo M, Legros F, Chateau D, Lombes A. Membrane topology and mitochondrial targeting of mitofusins, ubiquitous mammalian homologs of the transmembrane GTPase Fzo. J Cell Sci. 2002;115(Pt 8):1663–1674. PubMed

Malla B, Liotta A, Bros H, Ulshofer R, Paul F, Hauser AE, et al. Teriflunomide preserves neuronal activity and protects mitochondria in brain slices exposed to oxidative stress. Int J Mol Sci. 2022;23(3):1538. PubMed PMC

Miret-Casals L, Sebastian D, Brea J, Rico-Leo EM, Palacin M, Fernandez-Salguero PM, et al. Identification of new activators of mitochondrial fusion reveals a link between mitochondrial morphology and pyrimidine metabolism. Cell Chem Biol. 2018;25(3):268–78 e4. PubMed

Pellattiero A, Scorrano L. Flaming mitochondria: the anti-inflammatory drug leflunomide boosts mitofusins. Cell Chem Biol. 2018;25(3):231–233. PubMed

Magalon K, Le Grand M, El Waly B, Moulis M, Pruss R, Bordet T, et al. Olesoxime favors oligodendrocyte differentiation through a functional interplay between mitochondria and microtubules. Neuropharmacology. 2016;111:293–303. PubMed

Iwata K, Scorrano L. Finding a new balance to cure Charcot-Marie-Tooth 2A. J Clin Invest. 2019;129(4):1533–1535. PubMed PMC

Pfeuffer S, Kerschke L, Ruck T, Rolfes L, Pawlitzki M, Albrecht P, et al. Teriflunomide treatment is associated with optic nerve recovery in early multiple sclerosis. Ther Adv Neurol Disord. 2021;14:1756286421997372. PubMed PMC

Zhan J, Mann T, Joost S, Behrangi N, Frank M, Kipp M. The cuprizone model: dos and do nots. Cells. 2020;9(4):843. PubMed PMC

Kabiraj P, Grund EM, Clarkson BDS, Johnson RK, LaFrance-Corey RG, Lucchinetti CF, et al. Teriflunomide shifts the astrocytic bioenergetic profile from oxidative metabolism to glycolysis and attenuates TNFalpha-induced inflammatory responses. Sci Rep. 2022;12(1):3049. PubMed PMC

Silva Oliveira M, Schira-Heinen J, Reiche L, Han S, de Amorim VCM, Lewen I, et al. Myelin repair is fostered by the corticosteroid medrysone specifically acting on astroglial subpopulations. EBioMedicine. 2022;83:104204. PubMed PMC

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